This is an R01 proposal for a 3-year study of co-occurring mental and substance use disorders using the National Epidemiologic Study on Alcohol and Related Conditions (NESARC). The primary purpose of the proposed study is to examine the pathways from pure to, and among, co-occurring mental and substance use disorders in the population. More specifically, we will (1) identify profiles of pure and co-occurring mental and substance use disorders; (2) establish the temporal sequence of disorders within the identified profiles to generate the pathways to, and among, co-occurring disorders; (3) estimate the transition probabilities along these pathways and assess their variation by gender, age, and race/ethnicity; (4) estimate the impact of treatment of primary disorders on the probability of transitioning along these pathways to secondary disorders; and (5) estimate the economic consequences associated with different profiles of and pathways among co-occurring disorders. Two of the NESARC's most notable strengths (i.e., rigorous measurement of disorders and large sample size) make this novel approach to studying co-occurring disorders possible. The approach builds from published findings on the structure of common psychiatric disorders and the epidemiology of dual diagnoses to provide the first systematic research on the primary pathways to, and among, multiple co-occurring disorders. Addressing these questions will shed light on (1) the natural course of comorbidity and fill descriptive and etiologic gaps in our understanding of the risk of transitions between multiple disorders, (2) the impact of treatment on the risk of transitions to secondary disorders, and (3) the degree to which particular profiles of and pathways to co-occurring disorders influence personal economic outcomes. These pathways may constitute distinct subtypes of comorbidity and be targets for future epidemiologic, genetic, and treatment trial research. Thus, the results of this study will build a strong platform for probing subsequent research on the etiology and prevention of secondary mental and substance use disorders, addressing the patient population for whom the personal and societal costs of these disorders are the greatest.